Nearly one in every seven adults in America has chronic kidney disease (CKD), representing a 30% increase in the past decade. Individuals with advanced CKD are at extraordinarily high risk for loss of kidney function, cardiovascular events, and death, and cardiovascular disease is the leading cause of death in people with CKD. While much is unknown about why cardiovascular risk in individuals with CKD is so high, we and others have demonstrated that CKD is associated with increased systemic inflammation, elevated free fatty acids, and oxidative stress that lead to dysfunction of the endothelium. We and others have shown that high density lipoproteins (HDL) contain factors that reduce the level of activation and dysfunction of endothelial cells in vitro. Moreover, there is evidence that HDL from patients with CKD is altered in composition and function, which may directly cause endothelial dysfunction and lead to atherosclerosis and worsening kidney function. We have developed novel mass spectrometric methods to assess HDL composition and cell-based assays to assess the ability of HDL to preserve endothelial cell function. The combination of these assays provides for a comprehensive investigation of the molecules that contribute to HDL's anti-inflammatory capacity. Our overall hypothesis is that CKD causes changes to HDL composition and that these changes lead to increased endothelial dysfunction and greater risk of glomerular loss and cardiovascular disease (CVD). We also hypothesize that diet and exercise, an intervention that improves endothelial function in vivo, will lead to beneficial changes in HDL composition. Our goal is therefore to better understand the association of changes in HDL composition and function with endothelial dysfunction and clinical outcomes. We will take advantage of three well-characterized, NIH-funded clinical studies to elucidate the mechanisms behind HDL's ability to preserve endothelial cell function. To achieve these objectives, we propose the following aims: 1) Comprehensively characterize HDL composition and function in the CKD population; 2) Identify and quantify the changes in HDL composition and function that are associated with cardiac events, progression of kidney disease, and death; and 3) Determine whether healthy lifestyle interventions modify HDL composition and restore its anti-inflammatory properties in CKD subjects. This proposal will identify the molecular changes in HDL in subjects with CKD and how they are associated with endothelial dysfunction in vitro and in vivo. Moreover, our studies will identify the changes in HDL composition that are associated with cardiovascular and renal outcomes in a population at greatly increased risk of death.